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Congenital or acquired control of the clotting mechanism resulting in a widespread thrombotic tendency. Protein C is a vitamin K-dependent serine protease zymogen that selectively inhibits factors Va and VIII:C in human plasma, and thus has an important anticoagulant role. It is associated with an increased tendency to thrombosis. It is either inherited or acquired: bacterial sepsis (especially of meningococcal origin), hepatic disease, disseminated intravascular coagulation, l-asparaginase therapy, nephrotic syndrome, conditioning therapy in bone marrow transplantation, warfarin-induced skin lesions.

Congenital Thrombotic Protein C Deficiency; Hereditary Thrombophilia; PC Deficiency; ProC Deficiency.

The addition of Protein C deficiency in the list of thrombotic diseases was suggested by J.H. Griffin in 1981.

Inherited forms: 1:200 to 1:300 for heterozygotes; 1:200,000 for homozygotes.

Autosomal dominant trait with variable expressivity. Gene map locus: 2q13-q14.

Inherited thrombophilia has been associated with abnormalities of antithrombin III, fibrinogen, and plasminogen. Protein C is a vitamin K-dependent serine protease anticoagulant factor. It has several roles: (a) it is converted on site and on demand during the coagulation activation into activated protein C; its anticoagulant activity is related to inactivation of factors Va and VIIIa; the presence of protein S as a nonenzymatic cofactor is necessary for those reactions; (b) it promotes fibrinolysis by binding plasminogen activator inhibitor I; (c) it prevents the proinflammatory consequences of local thrombin formation, for example, release of vasoactive proinflammatory factors (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, etc.), and an increase of endothelial permeability. Consequently, a deficiency in protein C results in defective control of the clotting mechanism with a widespread thrombotic tendency. Heterozygotes show an increased thrombotic tendency, whereas homozygotes present with severe thrombotic sequelae in the neonatal period. Most cases of protein C deficiency have had a quantitative defect in the protein C molecule. Protein C deficiency with a mutation that causes diminished synthesis of protein has been referred to as type I and that with synthesis of a dysfunctional molecule as type II.

Positive family history and a significant history of thrombosis or gangrene (skin, retinal, etc.). Severe symptoms typically develop when the serum protein C level is below 20 to 25% of normal (4 μg/mL). Specific laboratory tests and assays are needed to exclude other causes of disseminated intravascular coagulation.

Heterozygotes for Protein C Deficiency (serum concentrations 40 to 60% of normal) usually presents in adolescence with recurrent thrombophlebitis, deep venous thrombosis, and pulmonary thromboembolism. There is also an increased risk of thrombotic renal and cerebral disease and an increased risk of myocardial infarction.

Homozygotes manifest fatal thromboses in the neonatal period—massive subcutaneous thrombosis (neonatal purpura fulminans) with cutaneous necrosis, gangrene, and widespread venous thrombosis, which usually starts in the first 24 hours of life. Severe bilateral vitreous hemorrhages, gangrene, and widespread venous thrombosis have been reported. Bilateral adrenal hemorrhage may lead to abdominal pain, hypotension, and hyponatremia. Hypertension and ...

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